INTRODUCTION — Anemia is common among patients with chronic kidney disease (CKD), including those on dialysis. Anemia underlies many of the symptoms associated with reduced kidney function and is associated with increased mortality and hospitalizations [1-4]. Iron deficiency is the most common reversible cause of anemia among such patients.
This topic reviews methods to diagnose iron deficiency in individuals with CKD. The treatment of iron deficiency in nondialysis CKD, peritoneal dialysis, and hemodialysis patients is discussed elsewhere. (See "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients" and "Treatment of iron deficiency in dialysis patients".)
Overall approaches to anemia in nondialysis CKD, peritoneal dialysis, and hemodialysis patients are discussed elsewhere. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Treatment of anemia in patients on dialysis".)
DEFINITIONS — Patients may have either absolute or functional iron deficiency.
●Absolute iron deficiency – Absolute iron deficiency is defined by severely reduced or absent storage iron in bone marrow.
●Functional iron deficiency – Functional (or relative) iron deficiency is characterized by adequate iron stores (defined by stainable iron in bone marrow) but insufficient iron availability for incorporation into erythroid precursors [5,6].
Functional iron deficiency is related in part to the administration of erythropoiesis-stimulating agents (ESAs). Among such patients, total body iron stores are adequate, but iron release from these stores into the circulation is not rapid enough to provide sufficient iron to support the increased erythropoietic rate being driven by the ESA.
However, many CKD patients also have anemia of chronic disease, which is related to an underlying inflammatory state [7]. Anemia of chronic disease is mediated in part by upregulation of hepcidin by inflammatory cytokines [8,9]. Hepcidin is a hormone that is produced and secreted by the liver and inhibits release of iron from reticuloendothelial macrophages and hepatocytes into plasma [6]. Hepcidin levels are increased in CKD patients [10-13].
It is clinically important to determine whether functional iron deficiency is related to ESA therapy or to anemia of chronic disease with an "inflammatory blockade" of available iron. However, it is often difficult to distinguish between these possibilities. The distinction is often made retrospectively after observing the erythropoietic response to administration of intravenous iron with or without a concomitant increase in ESA dose.
Functional iron deficiency related to ESA administration may respond to intravenous iron, while anemia of chronic disease is probably less likely to improve. The response to intravenous iron and an increase in ESA dose among patients thought to have functional iron deficiency was examined in the Dialysis Patients' Response to Intravenous Iron with Elevated Ferritin (DRIVE) study in which 134 patients with anemia, elevated ferritin levels (500 to 1200 ng/mL), low transferrin saturation (TSAT) levels (≤25 percent), and high ESA requirements were randomly assigned to ferric gluconate or placebo along with a 25 percent increase in ESA dose [14]. At six weeks, hemoglobin (Hb) levels had increased significantly more in the active-therapy group (1.6 versus 1.1 g/dL) [15]. Clinical outcomes beyond an increase in Hb level were not assessed, and the long-term safety of this approach is not established.
Diagnostic tests for absolute and functional iron deficiency are discussed below.
COMMONLY USED TESTS — Ideally, diagnostic tests for anemia should detect iron deficiency (both absolute and functional) and predict whether patients will respond to administered iron. There is no single test that does both.
The gold standard for the diagnosis of iron deficiency is measurement of iron stores in bone marrow obtained on biopsy (see "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'). However, bone marrow biopsies to assess iron stores are rarely done in CKD patients. Instead, iron stores are more commonly estimated by:
●Measurement of serum iron, total iron-binding capacity (TIBC), and ferritin and calculation of the percent transferrin saturation (TSAT)
or by
●Determination of the percentage of hypochromic red blood cells (HRCs) and determination of the reticulocyte hemoglobin (Hb) content (CHr)
In the United States, measurement of the serum iron, TIBC, and ferritin and TSAT is more commonly used. The percentage of HRC and Hb content tests may be more extensively used in Europe but are not widely available or used in the United States. (See 'Percent hypochromic HRCs and reticulocyte hemoglobin content' below.)
Both approaches are discussed below.
Serum iron, total iron-binding capacity, ferritin, and transferrin saturation — Measurement of these parameters is commonly used to identify iron deficiency. Laboratory criteria used to define iron deficiency and provide indication for treatment are markedly different among CKD patients compared with patients with normal kidney function. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnosis'.)
The TSAT and ferritin criteria are different for absolute and functional iron deficiency.
●Absolute iron deficiency – Among CKD patients, absolute iron deficiency, defined by diminished or absent bone marrow iron stores on biopsy, is likely to be present in patients when [16-19]:
•The percent TSAT (plasma iron divided by TIBC x 100) is ≤20 percent.
•The serum ferritin concentration is ≤100 ng/mL among patients with nondialysis CKD or those receiving peritoneal dialysis, or is ≤200 ng/mL among patients receiving hemodialysis. This difference in the serum ferritin level is based upon evidence in hemodialysis patients that the maintenance of ferritin levels >200 ng/mL is associated with decreased erythropoietin requirements.
By comparison, patients with normal kidney function and severe iron deficiency anemia typically have a serum ferritin concentration <30 ng/mL. The ferritin is commonly higher among iron-deficient CKD patients because it increases in response to diffuse inflammation, which characterizes advanced renal failure and dialysis [20,21]. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Inflammation in patients with kidney function impairment".)
When the ferritin is above 100 to 200 ng/mL, most patients will have stainable bone marrow iron that would be considered sufficient among patients without CKD.
However, among hemodialysis patients, neither the TSAT nor serum ferritin accurately predicts which patients will have an improved response to ESAs after iron supplementation [22]. Many hemodialysis patients with TSAT 20 to 30 percent and serum ferritin 200 to 500 ng/mL will respond to supplemental iron administration with an increase in Hb level and/or reduction in ESA dose [18,19].
As a result, such patients are commonly treated with iron prior to treatment with an ESA. Despite the fact that patients with TSAT >30 percent and ferritin >500 ng/mL are unlikely to respond to iron supplementation, intravenous iron supplementation for such patients is common in the United States. Some clinicians continue to administer intravenous iron supplementation even among patients with a serum ferritin >800 ng/dL.
●Functional iron deficiency – As noted above, in addition to absolute iron deficiency, hemodialysis patients may also have functional iron deficiency related to ESA administration or to anemia of chronic disease. (See 'Definitions' above.)
Both ESA-induced functional deficiency and anemia of chronic disease are characterized by TSAT that is commonly ≤20 percent and elevated ferritin levels (as high as 800 ng/mL or even higher). Patients with ESA-induced functional iron deficiency may respond to intravenous iron in association with a concomitant increase in ESA dose with a decrease in ferritin levels.
By contrast, anemia of chronic disease is most likely present if the weekly administration of intravenous iron (50 to 125 mg) for up to 8 to 10 doses fails to result in increased erythropoiesis; instead, this course of iron therapy typically results in a progressive increase in ferritin concentration.
Oral iron administration is of little or no value in distinguishing absolute or functional iron deficiency from inflammatory states since iron absorption is low in all of these conditions and oral iron is generally ineffective in treating anemia in dialysis patients. (See "Treatment of iron deficiency in dialysis patients", section on 'Dosing and administration'.)
Percent hypochromic HRCs and reticulocyte hemoglobin content — The percent hypochromic red blood cells (HRCs) and the CHr estimate the Hb content of red blood cells, not the amount of stored iron. As a result, they are more sensitive indicators of functional iron deficiency and are as good as or possibly better than the serum iron, TSAT, and ferritin at predicting whether or not a patient will respond to iron administration. A meta-analysis performed for the 2016 National Institute for Health and Care Excellence (NICE) guidelines demonstrated that HRC >6 percent predicted patients who would respond to iron as well as a TSAT <20 percent and ferritin <100 ng/mL [23]. The negative predictive value was better with percent HRC compared with TSAT and ferritin. However, the studies comprising the meta-analysis are limited, and comparisons with TSAT <20 percent and ferritin >100 ng/mL are lacking.
Both percent HRC and CHr can be assessed by flow cytometry, although not all laboratories have the capacity to perform the analysis [24-28].
The following thresholds are used to diagnose iron deficiency [23]:
●Percent HRC >6 percent
●CHr <29 pg
The NICE guidelines thus recommend that iron deficiency be diagnosed using HRC or CHr.
●In order for the percent HRC to be accurately measured, blood samples must be processed within six hours to prevent red cell swelling. Most outpatient dialysis facilities in the United States do not use this test for this reason. NICE guidelines recommend use of CHr if testing within six hours is not possible.
●Neither the percent HRC nor the CHr can be used in individuals with hemoglobinopathies such as thalassemia or thalassemia trait, which are characterized by decreased Hb production [23]. The NICE guidelines recommend use of TSAT and ferritin in such patients (but not either alone).
In addition, neither the percent HRC nor the CHr distinguishes functional from absolute iron deficiency.
Other — Measurement of serum hepcidin levels has also been examined for utility in assessing possible responsiveness to supplemental iron but remains experimental at this time [29,30].
DIAGNOSIS AND INDICATIONS FOR TREATMENT — The thresholds for treating CKD patients with iron vary according to patient group and are discussed separately.
●For nondialysis CKD patients (see "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients", section on 'Indications for treatment')
●For patients on hemodialysis (see "Treatment of iron deficiency in dialysis patients", section on 'Indications')
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in chronic kidney disease".)
SUMMARY AND RECOMMENDATIONS
●Anemia is common among patients with chronic kidney disease (CKD), including those on dialysis. Iron deficiency is the most common reversible cause of anemia among such patients. (See 'Introduction' above.)
●Patients may have either absolute or functional iron deficiency. Absolute iron deficiency is defined by severely reduced or absent storage iron in bone marrow, liver, and spleen. Functional iron deficiency is characterized by adequate iron stores (defined by stainable iron in bone marrow) but insufficient incorporation into erythroid precursors. (See 'Definitions' above.)
●Among CKD patients, particularly those on dialysis, functional iron deficiency is related in part to the administration of erythropoiesis-stimulating agents (ESAs; which causes an erythropoietic rate that exceeds the release of iron from stores into circulation) and to the anemia of chronic disease. (See 'Definitions' above.)
●Among CKD patients, commonly used methods for the diagnosis of iron deficiency include:
•Measurement of serum iron, total iron-binding capacity (TIBC), and ferritin and calculation of the percent transferrin saturation (TSAT).
•Determination of the percentage of hypochromic red blood cells (HRCs) and determination of the reticulocyte hemoglobin content (CHr).
While measurement of iron stores in bone marrow obtained on biopsy is considered the gold standard for the diagnosis of iron deficiency, bone marrow biopsies are rarely performed among CKD patients. (See 'Commonly used tests' above.)
●In the United States, measurement of the serum iron, TIBC, and ferritin and TSAT is more commonly used although they are not highly accurate for determining total body iron stores or response to iron supplementation. The HRC and CHr may be more extensively used in Europe but are not widely available in the United States. (See 'Commonly used tests' above.)
